Imjj I Requirements for J^The Degree Of/Doctor of .^Philosophy of the Council for Na'tioharacademic Awards
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University of Plymouth PEARL https://pearl.plymouth.ac.uk 04 University of Plymouth Research Theses 01 Research Theses Main Collection 1979 STRUCTURE - ACTIVITY RELATIONSHIPS IN SOME HERBICIDAL FLUORENE DERIVATIVES HARTNELL, MICHAEL WILLIAM http://hdl.handle.net/10026.1/1838 University of Plymouth All content in PEARL is protected by copyright law. Author manuscripts are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author. STRUCTURE - ACTIVITY RELATIONSHIPS IN SOME HERBICIDAL FLUORENE DERIVATIVES BY MICHAEL WILLIAM HARTNELL B.Sc, C. Chem. ,M.R. I. C. Ph.D,._T}ffiSIS^ This thesis is submitted in partial fulfilment of the imjj i requirements for j^the degree of/Doctor of .^Philosophy of the Council for Na'tioharAcademic Awards... Sponsored by:' In collaboration with: The School of Environmental Chesterford Park Research Sciences Station Plymouth Polytechnic Fisons Limited Drake Circus Agrochemicals Division PLYMOUTH Nr.SAFFRON WALDEN Devon PL4 8AA Essex CBIO IXL January 1979 PLYMOUTH POLYtECHHIC LEARHiHB BESOURCES CEHTRE ACCIi. No. CLASS No. CONTENTS 1. INTRODUCTION 6 1.1 Morphactins 6 1.2 Effects of Morphactins 7 1.3 Chemistry of Morphactins 9 1.4 Objects of Research 11 2. THEORETICAL 13 2.1 Fluorene 13 2.2 Synthetic Methods 13 2.3 Structure 19 2.4 Properties 20 2.4.1 Oxidation 21 2.4.2 Hydrogenation 23 2.4.3 Electrophilic Substitution in the Benzenoid Rings 23 2.4.4 Substitution at the 9-Position 26 DISCUSSION 33 3.1 Chemistry of 9,9-Bishydroxymethylfluorene 33 3.2 Hydroxyl Modifications 37 3.2.1 Esters 37 3.2.2 Chloromethyl Derivatives 37 3.2.3 Miscellaneous Reactions 39 3.3 Ring Substituted Derivatives of 9,9-Bishydroxymethylfluorene 40 3.3.1 2-Nitro-9,9-bishydroxymethylfluorene 40 3.3.2 Halogen Substituents 42 3.3.3 Acetyl Substituents 42 3.3.4 4-Substituted Derivatives 43 3.4 Methyl 2-Chloro-9-hydroxymethylfluorene- 9-carboxylate 43 3.5 Biological Screening of 9,9-Bishydroxy- methylfluorene Derivatives 43 XH20H (21) Rl = R2 = R3 = H Similar hydroxymethylations are theoretically possible using a variety of substituted fluorenes. Consequently, although the level of (HCHO) ft- DMSO (11) (21) Scheme 6 activity of 9,9 - bishydroxymethylfluorene(21) was in all cases lower than that of Chlorflurecol Methyl(9) it v;as considered worthwhile to explore the structure-activity relationships in a series of hydroxy- methylated fluorenes with the object of producing a novel compound possessing enhanced morphactin-like activity- The objects of the work described in this thesis can therefore be stated as: 1) The synthesis of a series of derivatives of 9,9 - bishydroxy methylfluorene(21) containing ring substituents and/or modified hydroxyl groups. 11) A study of the herbicidal activities of such compounds in relation to their structure. 12 PLYMOUTH POLYTECHNIC "STRUCTURE - ACTIVITY RELATIONSHIPS IN SOf^E HERBICIDAL FLUORENE DERIVATIVES" by MICHAEL WILLIAM HARTNELL> B.Sc, C.Chem., M.R.I.C ABSTRACT OF THESIS Synthetic plant-growth regulators derived from fluorene-9-carbo)0'lic acid ('morphactins') are introduced and the literature on them is reviewed. Similar herbicidal activity has been found with 9,9-bishydroxymethylfluorene, a compound which can be obtained directly from the hydrocarbon fluorene. There follows a detailed review of the chemistry of fluorene and 9,9- bishydro)^methylfluorene. 9-Substituted and ring-substituted derivatives of this diol have been synthesised and their chemistry and biological activity are discussed. The hydro)^methylation of substituted fluorenes is possible on a small scale in suitable solvents which do not stabilise the corresponding radical anions. This radical anion formation, when it occurs, seriously reduces the yield of hydroxymethylated product. Acetonitrile as solvent and aqueous benzyl- trimethyl ammonium hydroxide as base were found to be a particularly useful system for these reactions. Methyl 2-chloro-9-hydro)0'methylfluorene-9-carboxylate was found to be the most active compound synthesised. It was concluded that a 9-carbo>:*'lic acid group is required for high activity. None of the compounds examined were found to be more active than 'chlorflurecoT, the commercial product. ! /i 1 i CONCLUSION 47 EXPERIMENTAL A9 5.1 General Procedures 49 5.2 Hydroxyl Modifications 49 5.3 Ring Substituted Derivatives 61 5.4 Methyl 2-chloro-9-hydroxymethylfluorene- 9-carboxylate 68 REFERENCES 70 APPENDICES 75 1. Biological Screening Results 75 2. Herbicide Screening Methods 78 ACKNOWLEDGetENTS I wish to record my thanks to ray supervisors, Dr. R.W. Hanson and Dr. G.T. Newbold for their help throughout this project. Thanks are also due to Dr. R. Adams and Dr. Wendy Vincent for help v;ith the e.s.r. investigations. Finally,! would like to thank the tyuists, particularly Mrs. I.K. East, for their efforts. ABSTRACT . ^. , _ Synthetic plant-growth regulators derived from fluorene-9- cerboxyli'c acid ('morphfictins') are introduced and the literature on them is reviewed. Similar herbicidal activity has been found with 9,9-bishydroxymcthii1 fluorene, a compound which can be obtained directly from the hydrocarbon fluorene. There follows a detailed review of the chemistry of fluorene and 9,9-bishydroxyraethylfluorene. 9-Substituted and ring-substituted derivatives of this diol have been synthesiscd-and their chemistry and biological activity are discussed. The hydroxymethylation of substituted fluorenes is possible on a srr.all scale in suitable solvents which do not stabilise tho corresponding radical anions. This radical anion formation,when it occurs,seriously reduces the yield of hydroxymethylated product. Acetonitrile as solvent and aqueous benzyltriraethylammonium hydroxide as base were found to be a particularly useful system for these reactions. Methyl 2-chloro-9-hydroxymethylfluorene-9-carboxyiate was found to be the most active compound synthesised. It was concluc'cd that a 9-carboxylic acid group is required for high activity. None of the compounds examined v^re found to be more active than 'chlorflurecol', the commercial product. 1. INTRODUCTION 1.1 MORPHACTINS The different factors contributing to the growth and development of plants are controlled by a group of naturally occurring chemicals collectively called the phytohormones Some or all of these hormones act together in regulating the various growth processes. The natural growth control mechanisms can be interfered with chemically by several different types of synthetic growth regulator, one class of which is derived from fluorene - 9 • 2 carboxylic acid(l) . R (1) = R^ = H, R^ = CO^H = R2 = R3 = H •^1 (11) (2) = CI, R^ = OH.R^ = CO^H (14) = H, R^ = OH.R^ = CO^H ^1 h (6) = R2 = H, R^ = CN (15) = H,R2= CI, R3 = CO^Cl ^1 (7) = H, R^ = OHjR^ = CN (18) = H,R2/R3 = 0 \ ^1 (8) = R^ = H.R^ = ONO^ (19) = R2 = H.R^ = CONH^ (9) = CljR^ = OHjR^ = CO^Hc (20) = R^ = H,R3 = CI (10) = HjR^ = OHjR^ = CO^Bu" In 1953 Wain reported that fluorene - 9 - carboxylic acid(l) was active in the tomato leaf epinasty test (a downward curvature of the leaf petiole) and Went's pea test (the curvature of pieces of pea stem slit longitudinally). A year later,Jones, Metcalfe and Sexton showed that this compound inhibited the geotropism of various seedlings (downward curvature of the roots under the influence of gravity). Furthermore they discovered that certain derivatives of this acid, particularly 2 - chloro - 9 - hydroxyfluorene - 9 - carboxylic acid(2), were effective at very much lower concentrations. Similar effects were shown by N - 1 - naphthylphthalamic acid (Naptalam, 3) and 2, 3, 5 - tri-iodobenzoic acid(TIBA, 4) Their hypothesis was that since growth was not inhibited all of CH2C02^ NHCO CO2H (5) these antigeotropic substances competed with the phytohormone auxin or indole - 3 - acetic acid (lAA, 5) in its lateral transport mechanism, a process which occurs in plants influenced by gravity. Whilst these compounds have been shown to interfere with the internal movement of auxin, it seems unlikely, because of their structural differences, that they would compete for any hypothetical indoleacetic acid transporting site. It was subsequently shown, in 1960, by workers at the Merck 2 6 7 Biological Research Laboratories, ' ' ' that derivatives of fluorene - 9- carboxylic acid{l) designated as raorphactins, exerted a pov/erful effect upon the growth and development of higher plants. Further research led to the discovery of other related active compounds, particularly 9 - cyanofluorene, 9 - cyano - 9 - hydroxyfluorene and 9 - fluorenyl nitrate (6,7,8). Two morphactins, methyl 2 - chloro - 9 - hydroxyfluorene - 9 - carboxylateCChlorflurecol Methyl, 9) and n - butyl 9 - hydroxyfluorene - 9 carboxylate(Flurecol Butyl, 10) were marketed as commercial products in 9 1965 ^. 1.2 EFFECTS OF MORPHACTINS The effects of morphactins on plants have been reviewed in detail by Schneider^^ and Ziegler^^. These active compounds are absorbed into the plant via the leaves and the roots to be subsequently translocated throughout the plant system. They become active in the Uegetative apex and -2 -7 meristematic tissues over a very wide range of concentration(10 to 10 mol.dm ) without any toxic side-effects . It is a feature of the morphactins that they have very little effect on organs which at the time of application are already developing. Their major effects are seen on new growth v/hich has developed after treatment. The appearance of symptoms is slow but progressive. Development of the plant in general is slowed down, growth of the main, axis is suppressed and branching occurs. However, the lateral shoots which are produced are stunted as well. The root system of the plant is similarly affected. The normal geotropism of roots and phototropism of shoots are affected too. When applied at the correct stage of growth, morphactins inhibit the development of flowers or cause premature shedding of the buds.